The Section has focused on defining the role of the central stress response, (hypothalamic pituitary adrenal, HPA, axis) in susceptibility to inflammatory disease and associated behavioral responses to stress. Animal studies analyze the mechanism underlying the association of differential inflammatory disease susceptibility, relative HPA axis hypo- and hyperresponsiveness and patterns of behavioral responses to stress in inflammatory disease susceptible and resistant Lewis (LEW/N) and Fischer (F344/N) rats. Intracerebroventricular (i.c.v.) hypothalamic transplantation and genetic segregation and linkage are used to define relationships between traits and to identify associated gene loci. Transplantation of F344/N or LEW/N hypothalamic tissue i.c.v. into LEW/N rats is associated with increased host hypothalamic CRH expression and plasma corticosterone responses and decreased peripheral inflammation, but does not affect ratios of peripheral blood T cells sub-types. Transplantation of neural tissue preferentially affects the exudate volume rather than white cell infiltration components of inflammation, and has a relatively non-specific effect on experimental autoimmune encephalomyelitis (EAE). The uncoupling of these components of inflammation suggests that each may be regulated by different neuronal factors, and that hypothalamic CRH and CNS factors may play a greater role in acute, innate inflammatory responses rather than the later memory phases of peripheral inflammatory and autoimmune responses. In genetic linkage studies in collaboration with Dr. Howard Jacob (Harvard Medical School), we have identified over 400 polymorphic microsatellite loci in LEW/N and F344/N rats. Preliminary F2 analyses indicate several loci linking to the inflammatory trait. Current studies focus on defining these linkages and defining linkages which segregate with the traits of HPA axis responsiveness and patterns of behavioral responses. In human subjects, we have developed a whole blood ex vivo assay for glucocorticoid sensitivity of cytokine responses, including LPS-induced IL-1beta, IL-6 and TNF and SEB-induced IL-4, IFNg and IL-10. Physiological conditions associated with variations in plasma cortisol, such as circadian rhythm, or 30 minutes of exercise at 90% VO2 max, differentially affect dexamethasone inhibition of IL-6, IL-1beta and TNF responses. Patients with multiple sclerosis show heterogeneous glucocorticoid sensitivity suggesting a sub-population of glucocorticoid- resistant m.s. patients. AIDS-related studies show variations in HPA axis responses in a murine model of AIDS, MAIDS (collaborators: Janet Hartley and Herbert Morse, NIAID).